Abstract- B-lineage acute lymphoblastic leukemia (B-ALL) arises by malignant transformation of a progenitor (pre-B) cell. Cure rates in adults remain low and treatment is complicated by support provided by the microenvironment to the leukemic cells, indicating an urgent need to better understand the factors that promote their survival. We found that B-cell-activating factor (BAFF) and its receptor BAFF-R are important for ALL survival. Both Philadelphia chromosome (Ph)- positive and Ph-negative ALL samples tested were positive for high BAFF-R cell surface expression. Recombinant BAFF supported survival of the ALL cells in the absence of stroma, and it significantly attenuated the rate of apoptosis caused by exposure to nilotinib, a drug used therapeutically to treat Ph-positive ALLs. In this proposal, we will investigate the signaling pathways elicited by BAFF, role of BAFF in mediating drug resistance and finally how we can target BAFF-R or BAFF signaling for specific killing of ALL cells. We already published the effectiveness of fusion toxin rGel/BLyS in killing ALL cells. We propose to use a novel afucosylated BAFF-R antibody to mediate antibody dependent cytotoxicity (ADCC) using allogenic or autologous natural killer (NK) cells.